Resistance to chemotherapeutic drugs is an ongoing problem that results in eventual treatment failures or suboptimal patient outcomes. In cancer cells treated with drugs to which they are sensitive, the stress response is the first step in the subsequent cascade leading to cell death (apoptotic, necrotic or autophagy). The recent availability of a sensing modality for monitoring the development of stress in viable cells makes possible the utilization of stress as a diagnostic tool. BioSense Technologies proposes the development of a new diagnostic assay to determine the chemosensitivity of BCR-ABL (+) leukemia cells to therapeutic agents in real-time using unprocessed blood or bone marrow samples. Because the initiation of the stress response is immediate, drug-resistant leukemia cells can be distinguished from drug-sensitive cells in real- time avoiding any need for traditional cell culture to obtain the same information. This ability to provide the most effective therapy for each patient will reduce treatment failures and result in overall improved patient outcomes. Importantly, because the approach monitors a property fundamental to all cells, it is directly applicable to all other cancer cells types including solid tumor cancers. Feasibility of the proposed approach will be demonstrated with established human myeloid and lymphoblastic (Ph+) cell lines both drug-sensitive and -resistant to tyrosine kinase inhibitors. A follow-on effort will focus on the development of prototype instrumentation and validate the approach through clinical testing. PUBLIC HEALTH RELEVANCE: The development of a real-time diagnostic tool for determining the sensitivity/resistance profiles of leukemia cells to therapeutic agents is a significant step towards the administration of personalized medicine and optimal patient outcomes. By addressing and overcoming a significant technical barrier (the ability to determine the effects of a therapeutic agent on a cancer cell rapidly) the proposed project enables drug-resistant cancer cells to be distinguished from drug-sensitive cells in real-time. The availability of this diagnostic tool will arm oncologists with knowledge on the most effective drugs for eliminating the cancer cells as well as monitoring the possible onset of drug resistance during the administration of treatment. These new capabilities will avoid the empirical prescription of cancer therapy and enable the start or modification of existing treatment choices as needed. While the technical approach is applicable to a spectrum of different cancer types and therapeutic agents, this project focuses on the chemosensitivity testing of leukemia cells to tyrosine kinase inhibiting agents and the identification of drug resistance as an initial demonstration of its feasibility.